Potassium Channels and Their Potential Roles in Substance Use Disorders

McCoy, Michael T.; Jayanthi, Subramaniam; Cadet, Jean Lud

doi:10.3390/ijms22031249

Cited by 21 publications

(17 citation statements)

References 127 publications

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“…Thus, changes in differentially hydroxymethylated regions and increased expression of specific potassium channels in the brain may suppress methamphetamine-taking behaviors in the presence of adverse consequences. These observations support the idea of using potassium channel activators to treat methamphetamine use disorder in humans [ 43 ]. A recent study by You et al .…”

Section: Roles Of Dna Methylation and Dna Hydroxymethylation In Metha...supporting

confidence: 83%

Epigenetic Landscape of Methamphetamine Use Disorder

Cadet

Jayanthi

2021

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: The persistence of the addiction phenotype in methamphetamine use disorder (MUD) suggests the potential presence of epigenetic changes and potential structural adaptations that may drive the manifestations of MUD in humans. In the present review, we discuss the evidence that documents the fact that methamphetamine exposure can cause changes in epigenetic modifications, including histone acetylation and methylation, as well as DNA methylation and hydroxymethylation in a complex manner that need to be fully dissected. Nevertheless, our work has demonstrated the existence of correlations between behavioral changes and epigenetic alterations during methamphetamine self-administration. We found that prolonged methamphetamine self-administration and contingent footshocks resulted in rats with compulsive drug-taking and abstinent phenotypes. In addition, rats that reduce their methamphetamine intake in the presence of punishment showed increased DNA hydroxymethylation in genes encoding potassium channels in their nucleus accumbens. Moreover, altered DNA hydroxymethylation in those genes led to an increase in their mRNA expression. Additional studies revealed decreased mRNA expression of histone deacetylases associated with increased histone acetylation and induced gene expression in the dorsal striatum. These changes were associated with a reduction in methamphetamine intake in response to contingent footshocks. More research is necessary in order to further dissect how pharmacological or genetic manipulations of identified epigenetic alterations and expression of potassium channels can impact methamphetamine-taking behaviors or relapse to methamphetamine-taking after long periods of abstinence. Investigations that use discovery approaches, such as whole-genome sequencing after chromatin immunoprecipitation, should accelerate our efforts to develop epigenetic therapeutic approaches against MUD.

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Section: Roles Of Dna Methylation and Dna Hydroxymethylation In Metha...supporting

confidence: 83%

Epigenetic Landscape of Methamphetamine Use Disorder

Cadet

Jayanthi

2021

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“…rs62103177 is an intronic variant in the potassium voltage-gated channel modifier subfamily G member 2 (KCNG2) gene, which has been suggested to have a role in substance use disorders. 23,50 In GTEx, this variant is also an expression quantitative trait locus in brain tissues for the nearby RBFA Downstream Neighbor (RBFADN) gene (p<6.1×10 −6 across 12 GTEx brain tissues). Additional evaluation of this variant and its function in brain are supported by these results.…”

Section: Discussionmentioning

confidence: 99%

Multi-trait genome-wide association study of opioid addiction:OPRM1and Beyond

Gaddis

Mathur

Marks

et al. 2021

Preprint

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Opioid addiction (OA) has strong heritability, yet few genetic variant associations have been robustly identified. Only rs1799971, the A118G variant in OPRM1, has been identified as a genome-wide significant association with OA and independently replicated. We applied genomic structural equation modeling to conduct a GWAS of the new Genetics of Opioid Addiction Consortium (GENOA) data and published studies (Psychiatric Genomics Consortium, Million Veteran Program, and Partners Health), comprising 23,367 cases and effective sample size of 88,114 individuals of European ancestry. Genetic correlations among the various OA phenotypes were uniformly high (rg > 0.9). We observed the strongest evidence to date for OPRM1: lead SNP rs9478500 (p=2.56×10-9). Gene-based analyses identified novel genome-wide significant associations with PPP6C and FURIN. Variants within these loci appear to be pleiotropic for addiction and related traits.

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“…The human skyblue network was enriched in components of synaptic membranes that regulate the activity of ionotropic receptors and transmembrane transporters (Fig. 5C), among them are potassium channels (e.g., KCNC2, KCNC4, and KCNK13) and glutamate receptor subunits (e.g., GRIA4 and GRIN3A) that have been previously implicated in the behavioral manifestation of addiction (47)(48)(49)(50)(51). Notably, the GO terms enriched in the corresponding mouse module (Fig.…”

Section: Conserved Gene Network In Cud and Mouse Cocaine Selfadminist...mentioning

confidence: 98%

Convergent abnormalities in striatal gene networks in human cocaine use disorder and mouse cocaine administration models

et al. 2023

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Cocaine use disorder (CUD) is an intractable syndrome, and rising overdose death rates represent a substantial public health crisis that exacts tremendous personal and financial costs on patients and society. Sharp increases in cocaine use drive the urgent need for better mechanistic insight into this chronic relapsing brain disorder that currently lacks effective treatment options. To investigate the transcriptomic changes involved, we conducted RNA sequencing on two striatal brain regions that are heavily implicated in CUD, the nucleus accumbens and caudate nucleus, from men suffering from CUD and matched controls. Weighted gene coexpression analyses identified CUD-specific gene networks enriched in ionotropic receptors and linked to lowered neuroinflammation, contrasting the proinflammatory responses found in opioid use disorder. Integration of comprehensive transcriptomic datasets from mouse cocaine self-administration models revealed evolutionarily conserved gene networks in CUD that implicate especially D1 medium spiny neurons as drivers of cocaine-induced plasticity.

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Potassium Channels and Their Potential Roles in Substance Use Disorders

Cited by 21 publications

References 127 publications

Epigenetic Landscape of Methamphetamine Use Disorder

Epigenetic Landscape of Methamphetamine Use Disorder

Multi-trait genome-wide association study of opioid addiction:OPRM1and Beyond

Convergent abnormalities in striatal gene networks in human cocaine use disorder and mouse cocaine administration models

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